Journal Article

Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells

Bauer, K, Clevenger, C V, Löffler, D, Fischer, G, Sinz, A, Kretzschmar, A K, Brocke-Heidrich, K, Schiene-Fischer, C, Horn, F, Blumert, C, Cvijic, H

2009

Overview

Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon- γ was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Apoptosis / Biological and medical sciences / Cell Biology / Cell Cycle / Cell Line / Cell Line, Tumor / Cell physiology / Cell Survival / Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes / Chromatin Immunoprecipitation / Cyclophilin A - genetics / Cyclophilin A - metabolism / Cyclophilins - genetics / Cyclophilins - metabolism / Cyclosporins / Cytokines / Flow Cytometry / Fundamental and applied biological sciences. Psychology / Genetic aspects / Genetics / Health aspects / Hematologic and hematopoietic diseases / Human Genetics / Humans / Immunoblotting / Immunodeficiencies. Immunoglobulinopathies / Immunoglobulinopathies / Immunopathology / Interleukin 6 / Interleukin-6 - pharmacology / Internal Medicine / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Localization / Luciferases - genetics / Luciferases - metabolism / Luminescent Proteins - genetics / Luminescent Proteins - metabolism / Medical sciences / Medicine / Medicine & Public Health / Microscopy, Fluorescence / Molecular and cellular biology / Multiple myeloma / Multiple Myeloma - genetics / Multiple Myeloma - metabolism / Multiple Myeloma - pathology / Nuclear transport / Oncology / original-article / Peptidylprolyl isomerase / Phosphorylation / Phosphorylation - drug effects / Physiological aspects / Protein Binding / Recombinant Fusion Proteins - genetics / Recombinant Fusion Proteins - metabolism / RNA, Small Interfering - genetics / Signal Transduction / STAT proteins / Stat1 protein / Stat3 protein / STAT3 Transcription Factor - genetics / STAT3 Transcription Factor - metabolism / Transcription / Transcriptional Activation - drug effects / Transfection / Tyrosine / γ-Interferon